Development of anti-lung cancer drugs overcoming drug resistance mediated by new molecules a drug efflux pump, breast cancer resistance protein (BCRP), and topoisomerase-I inhibitor

我们探索了乳腺癌耐药蛋白(BCRP)/ABCG2的一半ABC转运体是抗肺癌药物拓扑异构酶I抑制剂的相对特异性转运体(Biochem BiPhys Research Commun 280：1216-1223,2001)。此外，我们已经报道了BCRP/ABCG2直接与药物相互作用，然后通过使用质膜囊泡表达BCRP立即将它们输出细胞外(BioChemBiPhys Commun 288：827-832,2001)。为了探讨BCRP/ABCG2在肺癌中的临床意义，我们对BCRP在非小细胞肺癌(NSCLC)的临床标本和培养细胞中的表达和功能进行了分析。结果表明，非小细胞肺癌组织中BCRPmRNA的表达水平与BCRP的功能及对拓扑异构酶I抑制剂SN-38和Topotecan的敏感性显著相关，部分非小细胞肺癌组织表达了足量的…在上述研究的基础上，我们合成了约30个新的SN-38的衍生物，以期开发新的抗癌药物来克服BCRP介导的耐药性。对这些衍生物进行了生化测试，以确定它们是否利用质膜囊泡克服了抗性。因此，我们证明了低极性喜树碱衍生物是克服耐药性的有效先导化合物，并为发现新药提供了一种实用的方法(Int J Cancer 110：921-927,2004)。另一方面，为了逆转BCRP介导的耐药性，我们检测了新诺贝菌素，一种香豆素抗生素，在BCRP过度表达的癌细胞中的逆转作用。Novobiocin通过竞争性抑制BCRP功能显著增加了细胞内拓扑替康的积聚(Int J Cancer 108：146-151,2004)。研究结果表明，在临床可接受的浓度下，新诺贝菌素有效地克服了BCRP介导的耐药性。非常有趣的是，我们证明了一种治疗肺癌的新型分子靶向药物吉非替尼逆转了BCRP介导的癌细胞耐药性，并且吉非替尼是BCRP的底物(癌症研究报告65：1541-1546,2005)。然而，我们发现吉非替尼本身不被BCRP转运，使用表达BCRP.FR901228的质膜囊泡是一种新的His Tone脱乙酰酶(HDAC)抑制剂，并在多种癌细胞中显示出抗肿瘤作用。我们证明了FR901228在非常低的浓度下非常有效地抑制小细胞肺癌细胞和耐药亚细胞的增殖(Int J Cancer 104：238-242,2003)。此后，我们认为FR901228通过线粒体途径而不是死亡受体途径诱导caspase依赖的细胞凋亡(Mol Cancer Ther 3：1397-1402,2004)。考虑到BCL-2和BCL-XL在多药耐药中的可能作用，FR901228是治疗难治性和原发小细胞肺癌的有前途的药物。较少

We have explored that breast cancer resistance protein (BCRP)/ABCG2 of a half ABC transporter is a relatively specific transporter for topoisomerase I inhibitors of anti-lung cancer drugs (Biochem Biophys Research Commun 280:1216-1223, 2001). In addition, we have reported that BCRP/ABCG2 interacted directly with drugs and then immediately exported them out of cells, by using plasma membrane vesicles ovemxpressing BCRP (BiochemBiophys Res Commun 288:827-832, 2001). These findings were the first reports in biochemical analyses of BCRP.Thereafter, to explore the clinical role of BCRP/ABCG2 in lung cancer, we did expression and functional analyses of BCRP in clinical specimens and culture cells of non-small cell lung cancer (NSCLC). The results were that the levels of BCRP mRNA expression in the cell lines were significantly correlated with the BCRP function and the sensitivity to SN-38 and topotecan of topoisomerase I inhibitors, and that some NSCLC tissues expressed sufficient levels of … More the BCRP mRNA to confer drug resistance in vitro (Clin Cancer Res 9:3052-3057, 2003).Based on the above findings, to develop new anticancer drugs overcoming BCRP-mediated drug resistance, we synthesized about thirty of new derivatives of SN-38. These derivatives were biochemically tested whether they overcame the resistance by using plasma membrane vesicles. Consequently, we demonstrated that low-polarity camptothecin derivatives were potent lead compounds to overcome the resistance, and provided a practical approach to discover new drugs (Int J Cancer 110:921-927, 2004). On the other hand, to reverse BCRP-mediated drug resistance, we examined the reversal effects of novobiocin, a coumermycin antibiotic, in BCRP-over expressing cancer cells. Novobiocin significantly increased intracellular topotecan accumulation by competitive inhibition of BCRP function (Int J Cancer 108:146-151,2004). The findings suggested that novobiocin effectively overcame BCRP-mediated drug resistance at clinically acceptable concentrations. Very interestingly, we demonstrated that gefitinib of a novel molecular target drug for lung cancer reversed BCRP-mediated drug resistance in cancer cells and that gefitinib was a substrate for BCRP (Cancer Res 65:1541-1546, 2005). However, we found that gefitinib itself was not tranported by BCRP, using plasma membrane vesicles expressing BCRP.FR901228 is a novel his tone deacetylase (HDAC) inhibitor and shows antitumor effects in various cancer cells. We demonstrated that FR901228 inhibited proliferation of small-cell lung cancer cells and drug-resistant sublines very effectively at very low concentrations (Int J Cancer 104:238-242, 2003). Thereafter, we suggested that FR901228 induced caspase-dependent apoptosis via the mitochondrial pathway rather than the death receptor pathway (Mol Cancer Ther 3:1397-1402, 2004). Considering the possible contributions of BCL-2 and BCL-XL to multidug resistance, FR901228 is a promising agent in the treatment of refractory as well as primary small-cell lung cancer. Less